title: p53 inhibits mRNA 3' processing through its interaction with the CstF/BARD1 complex.
abstract: The mechanisms involved in the p53-dependent control of gene expression following DNA damage have not been completely elucidated. Here, we show that the p53 C terminus associates with factors that are required for the ultraviolet (UV)-induced inhibition of the mRNA 3' cleavage step of the polyadenylation reaction, such as the tumor suppressor BARD1 and the 3' processing factor cleavage-stimulation factor 1 (CstF1). We found that p53 can coexist in complexes with CstF and BARD1 in extracts of UV-treated cells, suggesting a role for p53 in mRNA 3' cleavage following DNA damage. Consistent with this, we found that p53 inhibits 3' cleavage in vitro and that there is a reverse correlation between the levels of p53 expression and the levels of mRNA 3' cleavage under different cellular conditions. Supporting these results, a tumor-associated mutation in p53 not only decreases the interaction with BARD1 and CstF, but also decreases the UV-induced inhibition of 3' processing, all of which is restored by wild-type-p53 expression. We also found that p53 expression levels affect the polyadenylation levels of housekeeping genes, but not of p21 and c-fos genes, which are involved in the DNA damage response (DDR). Here, we identify a novel 3' RNA processing inhibitory function of p53, adding a new level of complexity to the DDR by linking RNA processing to the p53 network.
authors.affiliation: Chemistry Department, Hunter College, City University of New York, New York, NY 10065, USA.
authors.forename: F I
authors.initials: FI
authors.lastname: Nazeer
authors.forename: E
authors.initials: E
authors.lastname: Devany
authors.forename: S
authors.initials: S
authors.lastname: Mohammed
authors.forename: D
authors.initials: D
authors.lastname: Fonseca
authors.forename: B
authors.initials: B
authors.lastname: Akukwe
authors.forename: C
authors.initials: C
authors.lastname: Taveras
authors.forename: F E
authors.initials: FE
authors.lastname: Kleiman
mesh_terms: D002460:Cell Line; D039241:Cleavage Stimulation Factor / Q000502:physiology*; D006801:Humans; D012323:RNA Processing, Post-Transcriptional / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*
chemical_list: D039241:Cleavage Stimulation Factor; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C102449:BARD1 protein, human; D044767:Ubiquitin-Protein Ligases